Warfarin and various other Vitamin K-inhibiting medications (collectively known as coumarins; the terms coumarin(s) and warfarin are used interchangeably herein) are widely used anticoagulants and act by inhibiting the Vitamin K-associated carboxylation of coagulation factors II (prothrombin), VII, IX and X, as well as proteins S & C. Reduced clotting is indicated for patients with atrial fibrillation, heart valve implants, venous thromboembolism and other conditions, and an estimated 3 million people take coumarins in the US. Warfarin inhibits the enzyme vitamin KO reductase, which reduces the oxidized vitamin K epoxide (KO) to Vitamin K1 that is in turn reduced to vitamin KH2 by the warfarin-resistant vitamin K reductase. Vitamin KH2 is then available for carboxylation of glutamic acid residues in several proteins, including several coagulation factors. In the process, KH2 is oxidized to the epoxide. Therefore, it is noted that warfarin only affects the recycling of vitamin K and that its inhibition of Vitamin K metabolism can be overwhelmed by an increased intake of Vitamin K.
The coagulation cascade itself is measured as the PT or “Prothrombin time,” the time taken for plasma to clot following the addition of thromboplastin. Typically PT is expressed in terms of the INR, the International Normalized Ratio, which is used to standardize anticoagulant measurement between laboratories to account for reagent and process specific variations. INR is defined as:INR=(PTpt/PTnorm)ISI
where PTpt is the patient's prothrombin time measured in seconds, PTnorm is the prothrombin time for a pool of normal, untreated plasma, and ISI (International Sensitivity Index) characterizes the reactivity of the thromboplastin. An elevated INR (above a range of about 0.8 to 1.3) reflects a prolonged PT or slowed clot formation, which is the basis of warfarin's utility as a medicine. The therapy is usually geared to achieve a target INR range, typically 2.0≦INR≦3.0. Lower intensity anti-coagulation, with 1.5≦INR≦2.5 has been shown effective against deep vein thrombosis, accompanied by a reduction in bleeding complications, while higher intensity anti-coagulation, target range 2.5≦INR≦4.5, has been used with heart valve replacement.
Warfarin therapy results in a gradual lowering of the pool of clotting factors, based on their degradation in the body as fewer factors are produced. A loading dose of warfarin is not recommended since, although it lowers the prothrombin time more quickly, the high initial dose can lead to rapid depletion of Protein C, a short-lived clotting factor, and to excessive anti-coagulation. Bleeding is the primary danger of warfarin treatment, as detailed in an ongoing series of conference reports from the American Conference of Chest Physicians. Major bleeding occurs at a rate of 0.8%-2.0% per year in patients on warfarin, depending on the primary indication; this compares to a risk of serious thromboembolism in untreated patients with a first diagnosis of 7% per year. Fatality rates for patients on warfarin are on the order of 0.18% for extended therapy (over 6 months). The ACCP report emphasizes the result of variations in anti-coagulation as follows:
“. . . Increased variation in the anticoagulant effect, manifested by variation in the INR, is associated with an increased frequency of hemorrhage independent of the mean INR. This effect is probably attributable to the increased frequency and degree of marked elevations in the INR. Approaches to improve anticoagulant control (minimize INR fluctuations) could improve the safety and effectiveness of vitamin K antagonists . . . ”
The state of the art in anti-coagulation control is the skilled physician interpreting a series of INR measurements in the patient, and deciding whether to increase, leave unchanged, or lower the dose based on the last measurement. The second decision is then to fix the date of the next measurement, based on whether the current measurement was satisfactory, or to monitor the results of any changes in dose. When the INR is dangerously high, a physician may withhold doses of warfarin or prescribe one or more doses of Vitamin K to counteract the excess warfarin and to so lower the INR quickly, or to withhold warfarin and dose with Vitamin K.
Most physicians operate under a set of assumptions about warfarin, which is reflected in numerous reviews, published dosing algorithms and analysis of computer programs intending to replace subjective judgment of a physician. These key assumptions are as follows:                a. Warfarin takes time to act, but the effect of previous doses on the INR diminishes quickly with time.        b. The effect of warfarin is to inhibit the production of clotting factors. However, it should be noted that there are few studies on the quantitative relationship between Prothrombin Complex Activity and the INR, and that the time-course of the inhibition is poorly characterized.        c. The patient's sensitivity to warfarin changes fairly rapidly, making changing of the dose of warfarin an appropriate step where INR is high or low. Thus, withholding warfarin will bring down a high INR sufficiently quickly that it is preferred as an intervention. Lowering the warfarin dosage should lower the INR fairly quickly, so that if an INR remains high after a few days of the new lowered dosage, a further lowering is recommended.        d. The effects of a dose of Vitamin K are quick but transitory.        
For example, the recently published computer model ICAD reflects these assumptions and is unable to improve coagulation control in the clinic, even compared to the earlier and more primitive computer model TRODIS. In a clinical trial comparing these programs, 712 patients were randomized to either program and followed for a year with 12,000 INR tests. Patients on both programs were within a broad therapeutic range 80% of the time, which is consistent with a distribution of the INR typical of patients managed without advice from the computer models. Clearly, neither algorithm reduced INR variation. Moreover, as was shown in this study, patients spent 4% of their time with a low INR excursion and 16% of their time with a high INR excursion, indicating that the dosage of anti-coagulant was consistently too high. Both algorithms presented a suggested new dose to the attending physician as their primary output, which were rejected by the physician 20% of the time for ICAD and 9% of the time for TRODIS. However, TRODIS failed to make a suggestion and demanded physician input at 39% of visits, versus only 2% of visits for ICAD.
Such and other case studies strongly suggest that the above assumptions fail to properly reflect the pharmacokinetics of the coumarins and other factors. Moreover, as these assumptions also guide most practitioners in their treatment of patients, significant improvements are still to be realized.
In other known methods as described, e.g., in U.S. Pat. App. No. 2009/0216561, a patient's INR, a target INR, and prior cumulative dosage of anticoagulant during a treatment period is used to calculate a new dosage of anticoagulant for the next treatment period. While such method is conceptually simple and potentially reduces the frequency of over- and under-dosages, adjustment to a desired INR is typically slow. Moreover, accuracy may be less than desirable at higher INR values. In a further known method, as described in WO 2004/003550, metabolic phenotyping is used in INR maintenance. Such method provides new aspects of control, however, is typically unsuitable for initiation therapy and reduction of large INR variations. Alternatively, individualized coagulant dosages can be determined on the basis of polymorphisms in the VKORC1 gene, which is responsible for metabolizing warfarin as taught in WO 2006/044686. Additional analysis of CYP2C9 may further improve proper dosage prediction as disclosed in WO 2007/143617. While these methods tend to identify individual variations in warfarin metabolism, they nevertheless fail to reduce variability in INR, especially where the INR is relatively high.
Consequently, while many methods and devices are known to control INR, all or almost all of them suffer from one or more disadvantages. Thus, there is still a need to improve systems and methods of pharmaceutical intervention in coagulation control.